Cell adhesion, migration, and morphogenesis are crucial events in craniofacial development, and errors in them can result in congenital anomalies. Related biological processes appear to be important for normal adult wound repair and for tumor cell metastasis. We are characterizing proteins involved in these processes by structural and functional analyses. The extracellular matrix protein fibronectin is important for both morphogenesis and epithelial wound healing, e.g. for migration of craniofacial neural crest cells. We are exploring the roles of the nature of fibronectin anchorage to substrates on its effects on cell surface receptors and on the cytoskeleton. Collaborative molecular structural studies are also in progress to characterize further the requirements for fibronectin function. This information should facilitate the rational design of novel bioadhesives and inhibitors. The processes of cell adhesion, migration, and morphogenesis are regulated by a variety of factors, including transcription factors, kinases, and phosphatases. We are characterizing the roles of regulatory molecules such as the zinc- finger protein Slug in triggering epithelial-mesenchymal transition, which is a process essential for cranial neural crest cell migration. Slug is required for the first step of this process, triggering the loss of desmosomes and cell separation. Another potential regulatory molecule is the major new tumor suppressor PTEN, which is being characterized functionally in comparison with a homologous domain in tensin. We are participating in the NIDR Oral and Craniofacial Genome Project to discover new genes involved in embryonic development. Using subtraction approaches, we have identified a novel gene associated with epithelial- mesenchymal transition termed A4, which we are characterizing. We have also identified 18 novel genes specifically induced after adhesion of human salivary cells to fibronectin or collagen, but not to vitronectin. These studies should contribute to a molecular understanding of the regulation of these important but complex morphogenetic processes involving cell adhesion and the cytoskeleton.